1. Field of the Invention
This invention relates to a method, apparatus and product for non-invasively monitoring an actual system pressure within a mammal in space with time; to a method, apparatus and product for non-invasively assessing drug delivery and resistance to therapy of a tumor or organ within a mammal; to non-invasively control and/or suppress or reduce pressure in a tumor or organ; and to a method, apparatus and product for non-invasively mapping delivery capacity by imaging actual interstitial fluid pressure and/or concentration or distribution of a tracer.
2. Prior Art
With respect to the physiology and clinical application, the majority of cancer diseases are managed with a variety of systemic therapeutic agents. These agents are usually administered through the blood circulation, enter the tumor vasculature, extravasate out into the tissue across the microvascular wall and move through the interstitial compartment into the cells overcoming the cells membrane barrier. However, these therapeutic agents may not reach the target cells because of high pressure gradients that do not allow entrance of the drug to the tumor. This inhibition of delivery of drugs is a form of a physical drug resistance and can drastically impair treatment of tumors. Thus, a recurring question in the treatment of malignant tumors has been whether treatment failure is due to inadequate delivery or ineffective drugs. To find out whether there is no barrier to delivery one requires a method that can map the delivery capacity by imaging the distribution of a tracer (or contrast agent) under specific conditions.
Water soluble low molecular weight contrast agents are usually administered into the blood circulation. Upon reaching the tumor vasculature they are transferred across the walls of the capillaries into the tumor interstitial compartment. Once in the interstitial compartment they either return to the blood capillaries or enter the lymphatic drainage system or move through the interstitium towards the tumors surroundings. Each of these processes involves transfer by diffusion in the direction of the concentration gradients, as well as transfer by filtration or convection in the direction of the pressure gradients.
Transport Across the Microvascular Wall
A blood-borne molecule that enters the vascular system of an organ or a tumor, reaches the cells in the tissue (or tumor) via: a. distribution through the vascular compartment; b. transport across the microvascular wall; and c. transport through the interstitial compartment. For a molecule of given properties each of these transport processes may involve convection (i.e. solute movement associated with bulk solvent movement related to pressure gradients) and diffusion (i.e. solute movement resulting from solute concentration gradients).
Thus the extravasation Js(g/s) of a blood borne tracer occurs by diffusion and convection according to equation 1 below.Js=PS(Cp−Ci)+Lpσ[(PHν−PHi)−σT(Pν−Pi)]  (1)The first term describes the diffusion influence and the second term describes the pressure-convection influence. P (cm/s) is the vascular permeability coefficient, which is the proportionality constant that relates transluminal diffusion flux to concentration gradients. S (cm2) is the vessel's surface area, Cp−Ci is the agent concentration difference between the plasma and the interstitial space (g/m), Lp is the hydraulic conductivity which is the constant that relates fluid leakage to pressure gradientsPHν−PHi is the difference between vascular and interstitial hydrostatic pressure, σ (mmHg) is the osmotic reflection coefficient of the contrast agent which describes the effectiveness of the transluminal osmotic pressure difference in producing movement of the contrast agent across the vessel wall, σT is the average reflection coefficient of the plasma proteins (s˜1 for macromolecules and decreases towards zero as the molecular weight decreases) and Pv−Pi is the difference between the vascular and interstitial osmotic pressure.Transport Through the Interstitial Space
Once a molecule has extravasated from the microcapillary to the interstitium, its movement through the interstitial space occurs by diffusion and convection. Equation 2 quantifies this process:
                              J          i                =                                            -              D                        ⁢                                          ⅆ                C                                            ⅆ                x                                              -                      C            ⁢                                                  ⁢                          R              F                        ⁢            K            ⁢                                          ⅆ                p                                            ⅆ                x                                                                        (        2        )            
The first term describes the influence of the diffusion and the second term describes the influence of the convection on the movement of a molecule. D is the diffusion coefficient of the molecule in the interstitium, dC/dx is the concentration gradient, C is the molecule concentration, RF is its retardation factor, K is the tissue hydraulic conductivity for convective flow of water through the medium (K=k/ν where k is Darcy's constant (hydraulic conductivity) and ν is solvent viscosity) and dp/dx is the pressure gradient.
Jain and Baxter (1) derived the following partial differential equation that describes the changes with time in the contrast agent concentration in the extracellular-interstitial fraction
      ∂          C      i            ∂    t  for a spherical tumor with a radius r.
                                          ∂                          C              i                                            ∂            t                          =                                            D                              r                2                                      ⁢                          ∂                              ∂                r                                      ⁢                          (                                                r                  2                                ⁢                                                      ∂                                          C                      i                                                                            ∂                    r                                                              )                                -                                    r              f                        ⁢                          1                              r                2                                      ⁢                          ∂                              ∂                r                                      ⁢                                          (                                                      r                    2                                    ⁢                  K                  ⁢                                                            ⅆ                                              p                        i                                                                                    ⅆ                      r                                                        ⁢                                      C                    i                                                  )                            ++                        ⁢                                          P                ⁢                                                                  ⁢                S                            V                        ⁢                          (                                                C                  p                                -                                  C                  i                                            )                        ⁢            P            ⁢                                                  ⁢                                          l                v                            /                              (                                                      ⅇ                                          P                      ⁢                                                                                          ⁢                      l                      ⁢                                                                                          ⁢                      v                                                        -                  1                                )                                              +                                                                      L                  p                                ⁢                S                            V                        ⁢                                          (                                  1                  -                  σ                                )                            [                                                (                                                            p                      v                                        -                                          p                      i                                        -                                                                  σ                        T                                            ⁡                                              (                                                                              π                            v                                                    -                                                      π                            i                                                                          )                                                                              ]                                ⁢                                  C                  p                                                                                        (        1        )            
The first term on the right hand side is related to diffusion in the interstitial space which is determined by the tracer diffusion rate in the interstitial space D in units of cm2/s, the radial position in the tumor, r, and, the concentration gradient in
the interstitial space
                    ∂        C            ⁢                          ⁢      i              ∂      r        .
The second term describes the convection of the contrast agent in the interstitial space, which is determined by the retardation factor of the tracer, rf, the radial position in the tumor, the hydraulic conductivity of the interstitial fluid, K in units of cm2/mmHg·s and the pressure gradient in the interstitial space
                    ∂        p            ⁢                          ⁢      i              ∂      r        .
The third term reflects the diffusion due to concentration gradients across the capillary walls and is determined by the capillary permeability multiplied by the capillary surface area per unit volume PSN in units of s−1, the transcapillary concentration difference between the plasma and the interstitial compartment (Cp−Ci), and the Peclet number (Piv)—the ratio of convection to diffusion through the capillary wall.
The fourth term reflects the transfer due to pressure gradient across the capillary walls and is determined by the hydraulic conductivity of the capillary multiplied by the capillary surface area per unit volume LpS/V in units of (mmHg·s−1), the reflection coefficient of the contrast agent σ, The pressure difference between the intravascular and the interstitial spaces, (pv−pe), as well as by the average reflection coefficient of the plasma proteins, νT, multiplied by the osmotic pressure gradients between the plasma (νv) and the interstitial space (πi).
Theoretically it is possible to solve equation (1) under special boundary conditions and then fit a time course of the interstitial concentration to this equation. However, there are 10 free parameters that are unknown and hence, it is impractical to extract these parameters from a single time course. By using certain assumptions and approximations it is possible, however, to simplify the equation, and reduce the number of unknown parameters thereby make it possible to quantify the transfer properties of the contrast agent into and out from a tumor.
The first step in the simplification process is based on the assumption that the tumor can be divided into two regions a) a region in which the interstitial fluid pressure (IFP) is low and positive pressure gradients from the capillaries outwards favor extravasation of the contrast agent and b) a region in which IFP is high and the positive transcapillary pressure gradients are cancelled and replaced by negative gradients, which by convective transfer move the contrast agent in the interstitium to low IFP regions inside or outside the tumor. In both regions we also neglect the concentration dependent diffusion of the contrast agent in the tumor's interstitial space assuming that the exchange across the capillary walls by the concentration gradient is predominant.
The motion of the contrast agent in region (a) with low or negative IFP is determined by a diffusive transcapillary transfer constant
            P      ⁢                          ⁢      S        V    ⁢  P  ⁢          ⁢            l      v        /          (                        ⅇ                      P            ⁢                                                  ⁢            l            ⁢                                                  ⁢            v                          -        1            )      defined as ktrans, and a pressure dependent transcapillary extravasation constant
                    L        p            ⁢      S        V    ⁢            (              1        -        σ            )        [          (                        p          v                -                  p          i                -                              σ            T                    ⁡                      (                                          π                v                            -                              π                i                                      )                              ]      defined as kΔp and hence, the change in the concentration of the contrast agent in the interstitial compartment is given by
                                          ⅆ                          C              i                                            ⅆ            t                          =                                            k                              Δ                ⁢                                                                  ⁢                p                                      ⁢                          C              p                                +                                    k              trans                        ⁡                          (                                                C                  p                                -                                  C                  i                                            )                                                          (        2        )            
In order to solve this equation it is necessary to know the time dependent changes in the concentration of the contrast agent in the plasma (Cp(t)). For an instantaneous, bolus administration of the contrast agent this time course can be given by a biexponential decay (2) according to:Cp(t)=Ds(a1e−m1t+a2e−m2t)  (3)where Ds is the dose, a1 a2 are the amplitude of the components and m1 m2 are their rate constants (2).
Using a MRI contrast agent requires taking into account the fact that the MRI reflects the total amount of spins per voxel volume, Ct (assuming fast exchange of the water between the intra to extravascular compartments) rather than the amount per interstitial volume, namely the interstitial concentration (2) and therefore Ct=νe×Ci where νe is the extracellular volume fraction. The solution of 2 and 3 for Ct is therefore:
                                          C            t                    ⁡                      (            t            )                          =                              (                                          k                trans                            +                              k                                  Δ                  ⁢                                                                          ⁢                  p                                                      )                    ⁢          D          ⁢                                    ∑                              i                =                1                            2                        ⁢                                                            a                  i                                (                                                      ⅇ                                                                  -                                                                              k                            trans                                                                                υ                            e                                                                                              ⁢                      t                                                        -                                      ⅇ                                                                  -                                                  m                          i                                                                    ⁢                      t                                                                      )                                                              m                  i                                -                                                      k                    trans                                                        υ                    e                                                                                                          (        4        )            
The tumor tissue includes also the intravascular volume. Usually the intravascular volume fraction is low and can be neglected, but it is possible to add a term that describes the contrast agent concentration in this volume yielding the total tissue concentration of the contrast agent per unit volume of tissue.
                                          C            t                    ⁡                      (            t            )                          =                                            (                                                k                  trans                                +                                  k                                      Δ                    ⁢                                                                                  ⁢                    p                                                              )                        ⁢            D            ⁢                                          ∑                                  i                  =                  1                                2                            ⁢                                                                    a                    i                                    (                                                            ⅇ                                                                        -                                                                                    k                              trans                                                                                      υ                              e                                                                                                      ⁢                        t                                                              -                                          ⅇ                                                                        -                                                      m                            i                                                                          ⁢                        t                                                                              )                                                                      m                    i                                    -                                                            k                      trans                                                              υ                      e                                                                                                    +                                    υ              p                        ⁢            D            ⁢                                          ∑                                  i                  =                  1                                2                            ⁢                              a                i                                                      -                                          m                      i                                                        ⁢                  t                                                                                        (        5        )            where νp is the vascular volume fraction.
It is also possible to inject the contrast agent by slow infusion at a constant rate. For an i.v. infusion rate Dinf starting at time t=0, this injection can be treated as a series of small doses ΔD=DinfΔt′, each lasting time Δt′. The plasma concentration
                                          C            p            inf                    ⁡                      (            t            )                          =                                            lim                                                Δ                  ⁢                                                                          ⁢                                      t                    ′                                                  →                0                                      ⁢                                          ∑                                                      t                    ′                                    =                  0                                t                            ⁢                              Δ                ⁢                                                                  ⁢                                                      C                    p                                    ⁡                                      (                    t                    )                                                                                =                                    D              inf                        ⁢                                          ∑                                  i                  =                  1                                2                            ⁢                                                                    a                    i                                    ⁡                                      (                                          1                      -                                              ⅇ                                                                              m                            i                                                    ⁢                          t                                                                                      )                                                                    m                  i                                                                                        (        6        )            is the sum of the contributions from each doselet (3):
Thus for slow infusion the solution of Equation (2) using Equation (6) and adding the contribution of the vascular volume yields:
                                          C            t                    ⁡                      (            t            )                          =                                            D              inf                        ⁡                          (                                                k                  trans                                +                                  k                                      Δ                    ⁢                                                                                  ⁢                    P                                                              )                                ⁢                                    ∑                              i                -                1                            2                        ⁢                                                                                a                    i                                    ⁡                                      (                                                                                            1                          -                                                      ⅇ                                                                                          -                                                                  (                                                                                                            k                                      trans                                                                                                              v                                      e                                                                                                        )                                                                                            ⁢                              t                                                                                                                                                            k                            trans                                                                                v                            e                                                                                              -                                                                        1                          -                                                      ⅇ                                                                                          -                                                                  m                                  i                                                                                            ⁢                              t                                                                                                                                m                          i                                                                                      )                                                  /                                                      (                                                                  m                        i                                            -                                                                        k                          trans                                                                          v                          e                                                                                      )                                    ++                                            ⁢                              v                p                            ⁢                              D                inf                            ⁢                                                ∑                                      i                    =                    1                                    2                                ⁢                                                      a                    i                                    ⁡                                      (                                                                  1                        -                                                  ⅇ                                                                                    -                                                              m                                i                                                                                      ⁢                            t                                                                                                                      m                        i                                                              )                                                                                                          (        7        )            
The motion of a contrast agent in region (b) with high IFP is mainly determined by the diffusive transcapillary transfer and by pressure gradient dependent convective transfer in the interstitial volume. The convective transfer decreases the contrast agent concentration in these regions. The differential equation describing the change in the contrast agent concentration in these regions is: (kΔp has a negative sign)
                                                                        ⅆ                                  C                  i                                                            ⅆ                t                                      =                                                            -                                      k                                          Δ                      ⁢                                                                                          ⁢                      p                                                                      ⁢                                  C                  i                                            +                                                k                  trans                                ⁡                                  (                                                            C                      p                                        -                                          C                      i                                                        )                                                              ⁢                                          ⁢          Where          ⁢                                          ⁢                      k                          Δ              ⁢                                                          ⁢              P                                =                                    r              f                        ⁢                          1                              r                2                                      ⁢                                          ∂                                                                                              ∂                r                                      ⁢                          (                                                r                  2                                ⁢                K                ⁢                                                      ⅆ                                          p                      i                                                                            ⅆ                    r                                                              )                                      ⁢                                  ⁢        and        ⁢                                  ⁢                  k          trans                =                                            P              ⁢                                                          ⁢              S                        V                    ⁢          P          ⁢                                          ⁢                                    l              v                        /                          (                                                ⅇ                                      P                    ⁢                                                                                  ⁢                                          l                      v                                                                      -                1                            )                                                          (        8        )            
This differential equation, which includes space dependent and time dependent parameters, has no analytical solution. We therefore approximated the convective motion neglecting the space dependent component in Equation (8) and assuming that in all the pixels of this region (usually the inner parts of solid tumors) this term is similar, and hence kΔp=rfK (Δp), where Δp is the pressure difference that causes convection from a voxel of high IFP to a voxel of low IFP. With this approximated kΔp Equation (8) becomes a solvable first order differential equation. The solution of (8) (after conversion to Ct) for a bolus injection of the contrast agent, using Equation (3) and, including the contribution of the intravascular volume fraction is:
                                          C            t                    ⁡                      (            t            )                          =                                            k              trans                        ⁢            D            ⁢                                          ∑                                  i                  =                  1                                2                            ⁢                                                                    a                    i                                    (                                                            ⅇ                                                                        -                                                      (                                                                                                                            k                                  trans                                                                +                                                                  k                                                                      Δ                                    ⁢                                                                                                                                                  ⁢                                    p                                                                                                                                                              υ                                e                                                                                      )                                                                          ⁢                        t                                                              -                                          ⅇ                                                                        -                                                      m                            i                                                                          ⁢                        t                                                                              )                                                                      m                    i                                    -                                      (                                                                                            k                          trans                                                +                                                  k                                                      Δ                            ⁢                                                                                                                  ⁢                            p                                                                                                                      υ                        e                                                              )                                                                                +                                    υ              p                        ⁢            D            ⁢                                          ∑                                  i                  =                  1                                2                            ⁢                              ⅇ                                                      -                                          m                      i                                                        ⁢                  t                                                                                        (        9        )            
For administration of the contrast agent at a slow infusion rate the solution is:
                                          C            t                    ⁡                      (            t            )                          =                              D            inf                    ⁢                      k            trans                    ⁢                                    ∑                              i                -                1                            2                        ⁢                                                                                a                    i                                    ⁡                                      (                                                                                            1                          -                                                      ⅇ                                                                                          -                                                                  (                                                                                                                                                    k                                                                                  Δ                                          ⁢                                                                                                                                                                          ⁢                                          P                                                                                                                    +                                                                              k                                        trans                                                                                                                                                    v                                      e                                                                                                        )                                                                                            ⁢                              t                                                                                                                                                                                          k                                                              Δ                                ⁢                                                                                                                                  ⁢                                P                                                                                      +                                                          k                              trans                                                                                                            v                            e                                                                                              -                                                                        1                          -                                                      ⅇ                                                                                          -                                                                  m                                  i                                                                                            ⁢                              t                                                                                                                                m                          i                                                                                      )                                                  /                                                      (                                                                  m                        i                                            -                                                                                                    k                                                          Δ                              ⁢                                                                                                                          ⁢                              P                                                                                +                                                      k                            trans                                                                                                    v                          e                                                                                      )                                    ++                                            ⁢                              v                p                            ⁢                              D                inf                            ⁢                                                ∑                                      i                    =                    1                                    2                                ⁢                                                      a                    i                                    ⁡                                      (                                                                  1                        -                                                  ⅇ                                                                                    -                                                              m                                i                                                                                      ⁢                            t                                                                                                                      m                        i                                                              )                                                                                                          (        10        )            
In summary, approximated equations have been developed for the time dependent changes in the concentration of a contrast agent in tissues, specifically tumors. These equations that take into account concentration gradients across the capillary walls that lead to diffusive transcapillary transfer, pressure dependent gradients across the capillary walls that lead to filtrative (or extravasative) transcapillary transfer and pressure gradients within the interstitial compartment that lead to convective transfer within the interstitium from high IFP to low IFP.
In the case of a bolus injection of the contrast agent, in order to determine whether a voxel belongs to region (a) with low IFP or region (b) with high IFP, the MRI derived enhancement curves can be fitted to Equation 5 and Equation 9. The better fitting (assessed for example by calculating the higher value of proportion of variability, R2) provides a means to select the type of region ((a) or (b)) and the corresponding transfer constants.
In the case of slow infusion of the contrast agent, in order to determine whether a voxel belongs to region (a) with low IFP or region (b) with high IFP, the MRI derived enhancement curves can be fitted to Equation 7 and Equation 10, the better fitting ((a) or (b)) and the corresponding transfer constants.
Because the drop in the plasma concentration after a bolus injection is very fast, in parts of tumors' regions it is difficult to detect a transfer of constant agent (low or null enhancement). However, it is not clear whether the low or null transfer is due to low concentration dependent diffusive transfer across the capillary walls or to high IFP in the interstitium and outward convection. In contrast, when a slow infusion is used, the plasma concentration is continuously increasing reaching a maximum value at steady state (steady state is defined as the state when the rate of injection is equals the rate of clearance through the kidneys into the urine and hence the plasma concentration is constant). Hence, even if the concentration dependent diffusive transfer across the capillary walls is low the interstitium will be filled up at steady state and the low transfer constant can be determined. If, however there is no or low enhancement at steady state it is clear that the IFP is high in this region. Thus, the slow infusion enables determining the mechanism of contrast agent transfer ((a) or (b)) even when the diffusive transfer constant is low.
Interstitial Fluid Pressure (IFP)
Interstitial fluid pressure is the hydrostatic pressure of water in the extracellular extravascular compartment measured in mmHg. Normal tissues possess interstitial fluid pressure of (−2)-0 mmHg, while tumors often possess higher Interstitial Fluid Pressure of 10-50 mmHg. IFP in Tumors reaches high values due to:
1. The proliferation of cells in a confined area
2. High water permeability of the vascular wall
3. Lack of functioning lymphatic vessels and drainage of water.
4. Metabolic induced increase in IFP: The main metabolic event is enhanced glycolysis that produces two lactate molecules from one glucose molecule. Lacate molecules usually accumulate in the interstitial space, and thereby increase osmotic pressure.
5. Composition of the interstitial compartment which determines the interstitium elasticity and the interstitial fibers contractility and flexibility.
In the prior art it has been suggested that in the center of tumors interstitial fluid pressure (IFP) can exceed the vascular blood pressure while in the periphery it is lower than the vascular blood pressure. Consequently molecules mainly extravasate from blood vessels in the tumor periphery. Elevated interstitial fluid pressure changes the movement of molecules through the compartments leading to restrict accumulation of therapeutic agents in the tumors. Namely, elevated interstitial fluid pressure attenuates extravasation of drugs from capillaries to central regions of tumors, and creates convection of the drug from the tumor center outward, in the direction of the interstitial pressure gradient.
Modulation of Pressure Balance by Drugs
Few attempts were made in order to elevate drug concentration in tumors that exhibit high IFP. The strategy was to apply pharmaceutical agents that influence blood pressure and flow in order to increase extravasation to tumor tissues; however these studies were not aimed at improving delivery by reducing interstitial pressure.
Most of the experiments were performed on rodents bearing implanted tumor xenografts. Drugs of three major pharmaceutical groups were applied: vasoconstrictors, vasodilators and drugs that reduce blood viscosity.
IFP Measuring Methods
Currently, there are two main methods for measuring interstitial fluid pressure, Perforated capsule and Needle methods. These methods are not imaging methods and can measure pressure in limited loci in a tumor. The notable disadvantage of these methods is their invasiveness, which results in damaging the investigated tissue including elevating its interstitial fluid pressure. Furthermore, these methods cannot be used in internal organs and tumors.
Perforated Capsule (Micropore Chamber) Method
The capsule method employs a porous polyethylene capsule surgically implanted in the tissue to be studied. After several weeks, the fluid in the capsule reaches equilibrium with the surrounding interstitial fluid. The pressure of the fluid within the capsule is then measured with a pressure transducer. This method has the following disadvantages:
1. Surgical implantation is required and a prolonged period for equilibration. 2. The observed pressure is influenced by the osmotic gradient between the fluid inside and the fluid outside the capsule. 3. Implantation of the capsule can cause immune response, which changes the pressure of the tissue.Wick in Needle Method
The wick-in-needle technique consists of a hypodermic needle connected to a pressure transducer via tubing filled with saline. The needle is then placed in the tumor where the pressure is to be measured. The needle hole is filled with polyester or other fiber to improve the fluid communication between the probe and the tumor tissue. The pressure is increased until fluid flows into the tissue. The pressure at this point is considered to be equal to the interstitial fluid pressure. The pressure transducer converts the pressure to a voltage, which is logged by a computer. This method has some drawbacks: It can cause tissue distortion and trauma, as well as increase interstitial fluid pressure. Micropipettes and servo null device were used in order to overcome these disadvantages.
In a published article (4) it was reported that tumor response to blood borne drugs is critically dependent on the efficiency of vascular delivery and transcapillary transfer. However, increased tumor interstitial fluid pressure (IFP) forms a barrier to transcapillary transfer, leading to resistance to drug delivery. Presented was a new, noninvasive method which estimated IFP and its spatial distribution in vivo using contrast-enhanced magnetic resonance imaging (MRI). The method was tested in ectopic human non-small-cell lung cancer which exhibited a high IFP of ˜28 mm Hg and, for comparison, in orthotopic MCF7 human breast tumors which exhibited a lower IFP of ˜14 mm Hg, both implanted in nude mice. The MRI protocol consisted of slow infusion of the contrast agent [gadolinium-diethylenetriaminepentaacetic acid (GdDTPA)] into the blood for ˜2 hours, sequential acquisition of images before and during the infusion, and measurements of T1 relaxation rates before infusion and after blood and tumor GdDTPA concentration reached a steady state. Image analysis yielded parametric images of steady-state tissue GdDTPA concentration with high values of this concentration outside the tumor boundaries, ˜1 mmol/L, declining in the tumor periphery to ˜0.5 mmol/L, and then steeply decreasing to low or null values. The distribution of steady-state tissue GdDTPA concentration reflected the distribution of IFP, showing an increase from the rim inward, with a high IFP plateau inside the tumor. The changes outside the borders of the tumors with high IFP were indicative of convective transport through the interstitium. The article presented a noninvasive method for estimating and based thereon assessing the spatial distribution of tumor IFP and mapping barriers to drug delivery and transport. The main disadvantage of this proposed method is that it results in an estimate only.
The main drawback of the prior art is the inability to determine actual interstitial fluid pressure non-invasively.